Despite advances in both diagnosis and therapy, the annual number of cancer related deaths has not decreased during the past 60 years. Although conventional cancer therapies (surgery, radiotherapy, chemotherapy) produce a high rate of cure for patients with early stage disease, many cancers recur and the majority of patients with advanced cancer eventually succumb to the disease. The limitations of conventional cancer therapies do not derive from their inability to ablate tumor, but rather from limits on their ability to do so without excessively damaging the patient. It is this consideration that constrains the extent of surgical resection, the dose of radiation and volume to be irradiated, and the dose and combination of chemotherapeutic drugs. Improving the effectiveness of a treatment is of no clinical value if there is no significant increase in the differential response between tumor and normal tissue (i.e., therapeutic index).
Nonetheless, improved methods and novel agents for treating cancer have resulted in increased survival time and survival rate for patients with various types of cancer. For example, improved surgical and radiotherapeutic procedures result in more effective removal of localized tumors. Surgical methods, however, can be limited due, for example, to the location of a tumor or to dissemination of metastatic tumor cells. Radiotherapy also can be limited by other factors that limit the dose that can be administered. Tumors that are relatively radioresistant will not be cured at such a dose.
Although a single treatment modality such as radiation therapy, chemotherapy, surgery or immunotherapy can result in improvement of a patient, superior results can be achieved when such modalities are used in combination. In particular, treatment with a combination of radiotherapy, which can be directed to a localized area containing a tumor, and chemotherapy or immunotherapy, which provide a systemic mode of treatment, can be useful where dissemination of the disease has occurred or is likely to occur. Unfortunately, the therapeutic usefulness of radiation therapy can be limited where the tumor cells are relatively radioresistant, since the dose is limited by the tolerance of normal tissue in the radiation field. Thus, there exists a need to sensitize cancer tumors to the effects of radiotherapy so that it can more effectively reduce the severity of a tumor in a patient. Further, it would be useful to develop a treatment that more specifically isolates the location of the radiation, thus preventing the effects of radiation treatment on healthy cells.
In related fashion, to mitigate unwanted effects of some chemotherapies, adenovirus vectors have been used to transduce tumor cells with so-called “chemogenes” that convert a nontoxic substance, or “prodrug”, into a toxic, therapeutically effective form. Several new approaches involving gene therapy are under consideration for improving the therapeutic index of cancer therapies.
One of these approaches, so-called “suicide gene therapy,” involves the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic prodrugs into toxic anti-metabolites. Two “suicide genes” that are currently being evaluated in clinical trials are the E. Coli cytosine deaminase (CD) and herpes simplex virus type-1 thymidine kinase (HSV-1 TK) genes, which confer sensitivity to 5-fluorocytosine (5-FC) and ganciclovir (GCV), respectively. Following targeted transfer of these genes to the tumor, the 5-FC and GCV prodrugs are converted locally into potent chemotherapeutic agents resulting in significant tumor cell death (see reference 1 (and the references cited therein) in the List of References Section below). Thus, the dose-limiting systemic toxicity associated with conventional chemotherapies is mitigated.
Previously, the bacterial CD and wild-type HSV-1 TK genes have been coupled to create a novel CD/HSV-1 TK fusion gene (see reference (hereinafter “ref.”) 1 in the List of References Section). The CD/HSV-1 TK fusion gene allows for combined use of CD/5-FC and HSV-1 TK/GCV suicide gene therapies. It has been previously demonstrated that CD/5-FC and HSV-1 TK/GCV suicide gene therapies render malignant cells sensitive to specific pharmacological agents and importantly, sensitize them to radiation (see refs. 1-9). Using a novel, oncolytic, replication-competent adenovirus (Δd5-CD/TKrep) containing the prototype CD/HSV-1 TK fusion gene (ref. 10), the safety and efficacy of replication-competent adenovirus-mediated double suicide gene therapy without and with radiation therapy in several preclinical cancer models (refs. 10-13) and more recently, in human prostate cancer patients (refs. 14 and 15) have been demonstrated.
In these clinical trials targeting human prostate cancer, the Ad5-CD/TKrep virus proved to be safe up to a dose of 1012 Vp when combined with up to 3 weeks of 5-FC and GCV (vGCV) prodrug therapy without (ref. 14) and with (ref. 15) conventional dose (70 Gy) three dimensional conformal radiation therapy (3DCRT). Moreover, these treatment regimens have demonstrated signs of clinical activity (refs 14 and 15).
Nonetheless, despite these advances, a significant need remains for inventions that comprise effective methods and compositions for use in cancer therapies. The present invention was developed in light of these and other drawbacks.